The year 1996 marked one of modern medicine’s biggest milestones. For the first time, genetic screening for cancer risk became commercially available—in the form of Myriad Genetics’ test for the BRCA1/2 mutations linked to breast and ovarian cancer. Similar breakthroughs have since helped save countless patients, particularly those diagnosed with inherited diseases.
But not all genetic disorders have such clear-cut diagnostic biomarkers. One of these exceptions is exfoliation syndrome, a common age-related disorder where abnormal proteins progressively accumulate in the eye’s anterior chamber, causing glaucoma and irreversible blindness.
To identify these elusive genetic clues, Chiea Chuen Khor, a Senior Principal Investigator at the Genome Institute of Singapore (GIS), and his collaborators searched for potential markers for exfoliation syndrome across a dataset of protein-coding genetic variants.
The comprehensive study spanned twenty years and included over 20,000 participants across 14 countries. “Due to the rarity of disease-causing genetic variants, a large study sample size is needed to obtain enough statistical power to be certain of the results,” explained Khor.
Though techniques such as genome-wide association studies (GWAS) had been deployed to demystify this disorder, such methods have so far failed to yield significant breakthroughs. This time around, Khor and colleagues adopted a more sophisticated approach—using whole-exome sequencing, which takes into account the exome, or all the genome’s protein-coding regions.
By sequencing and comparing the exomes of individuals affected by exfoliation syndrome and healthy controls, the team finally found the needle in the haystack, pinpointing the CYP39A1 gene out of a pool of over 18,000 genes predicted to have impaired protein function.
“CYP39A1 emerged as the gene where a significant proportion of the affected individuals carried mutations compared to unaffected individuals,” noted Khor.
Normally, CYP39A1 produces an enzyme that metabolizes cholesterol into its derivatives. Because mutations resulting in the loss of CYP39A1 function strongly correlated with an increased risk of exfoliation syndrome, the team hypothesized that the deficient gene may also impair cholesterol metabolism—likely resulting in excess cholesterol accumulating in the eye.
“The smoking gun was found when we managed to stain cholesterol within the exfoliative material, confirming that cholesterol is part of the disease process as well,” commented Khor.
As the first study to present evidence that other biomolecules beyond proteins play a key role in exfoliation syndrome, their insights propel over two decades of research forward, spurring future studies on how to treat and possibly prevent the condition. Currently, the researchers are conducting follow-up studies to determine how different CYP39A1 variants influence the risk of blindness due to exfoliation glaucoma.